Process for producing {60 -amino penicillin intermediates

ABSTRACT

A method for preparing organosilane derivatives of Alpha -amino penicillins comprising preparation of an amine base salt of 6aminopenicillanic acid by reacting the latter with a strong amine in an organic solvent devoid of hydroxyl groups; adding to the resulting mixture of the amine base salt of 6-aminopenicillanic acid, which has had added thereto a weak amine base, a mono- or multi-functional halosilane; incorporating a mineral acid salt of a weak amine in the mixture; and then adding to the last resulting mixture the chloride hydrochloride of a suitable Alpha -amino acid to form by acylation the organosilane derivatives of the hydrochloride of the desired Alpha -amino penicillin. The resulting silylated and silenated penicillin hydrochlorides are useful for conversion into the corresponding Alpha -amino penicillin having potent antibiotic activity, by simple hydrolysis or alcoholysis, followed either by transformation of the resulting penicillin hydrochloride into an aryl sulfonic acid salt thereof which may be neutralized to the penicillin per se by addition of a suitable base, or by the raising of the pH of the reaction mixture to the iso-electric point to cause precipitation of the desired penicillin.

United States Patent Robinson [54] PROCESS FOR PRODUCING a-ANIINOPENICILLIN INTERMEDIATES [72] Inventor: Charles A. Robinson, WestChester, Pa.

[73] Assignee: American Home Products Corporation,

New York, N.Y.

[22] Filed: Aug. 10, I970 |2I| Appl. No.: 62,682

Related US. Application Data [63] Continuation-in-part of Ser. No.4,l6l, Jan. 14. i970, abandoned, Continuation of Ser. No. 671,938, Oct.2, i967, abandoned.

Primary Examiner-Nicholas S. Rizzo Arlorney-Andrew Kafko. Joseph MartinWeigman, Dwight L Potter, Vito Victor Bellino and Robert Wiser July 18,1972 ABSTRACT A method for preparing organosilane derivatives of a-aminopenicillins comprising preparation of an amine base salt of 6-aminopenicillanic acid by reacting the latter with a strong amine in anorganic solvent devoid of hydroxyl groups; adding to the resultingmixture of the amine base salt of 6 aminopenicillanic acid, which hashad added thereto a weak amine base, a monoor multi-functionalhalosilane; incorporating a mineral acid salt of a weak amine in themixture; and then adding to the last resulting mixture the chloridehydrochloride of a suitable a-amino acid to form by acylation theorganosilane derivatives of the hydrochloride of the desired a-aminopenicillin. The resulting silylated and silenated penicillinhydrochlorides are useful for conversion into the corresponding a-aminopenicillin having potent antibiotic activity, by simple hydrolysis oralcoholysis, followed either by transformation of the resultingpenicillin hydrochloride into an aryl sult'onic acid salt thereof whichmay be neutralized to the penicillin per se by addition of a suitablebase, or by the raising of the pH of the reaction mixture to theiso-electiic point to cause precipitation of the desired penicillin.

l7 Claims, No Drawings BACKGROUND OF THE INVENTION This inventionrelates generally to the preparation of aamino penicillins having potentantibiotic activity, and more particularly to a novel process forpreparing the silylated and silenated forms of certain a-aminopenicillin hydrochlorides defined hereinafter, which are easilyconvertible to the desired a-amino penicillins per se by hydrolysis oralcoholysis, followed by transformation of the resulting penicillinhydrochloride into an aryl sulfonic acid salt thereof which may beneutralized to the penicillin per se by addition of a suitable base, orby the raising of the pH of the reaction mixture to the iso-electricpoint to cause precipitation of the desired penicillin.

The so-called "silyl" route to the production of penicillins is nowgenerally known. For example, in US. Pat. No. 3,249,622 there isdisclosed a process for preparing penicillins generally by said "silyl"route. However, the process therein disclosed is not particularlyadapted to the preparation of amino penicillins. Moreover, for thepreparation of silylated 6- amino-penicillianic acid, which is later tobe acylated, the patent states a preference for hydrocarbons and ethersas solvents. There is no suggestion at all that other types of organicsolvent devoid of hydroxyl groups may be advantageously substituted.Furthermore, in all the Examples given in the patent, in whichtrimethylchlorosilane is used as silylating agent, there is shown theuse of benzene or toluene as solvent, and the need for reflux for 5hours (at 80-l l0C) to form the silylated b-aminopenicillanic acid.

ln Glombitza, Annalzn 673, 166(l964) there is disclosed the preparationof penicillins (similarly not including a-amino penicillins) by a silyl"route using assilylating agent hexamethyldisilazane in chloroform. Theuse of hexamethyldisilazane for the preparation of silylated6-aminopenicillanic acid has the disadvantage that the by-productammonia formed in the reaction must be completely removed beforeproceeding to the acylation step.

In Irish Pat. No. 7463 (which matured from application No. l02/63),there is disclosed an extension of the silyl route to the preparation ofa-amino penicillins. Therein, for the preliminary preparation of therequisite silylated 6- aminopenicillanic acid, preference is disclosedfor heating 6- aminopenicillanic acid with more than two moles of N-trimethylsilyldiethylamine at 60"-l 70C so that diethylamine distillsoff. Moreover, excess N-trimethylsilyldiethylamine must be removed byvacuum distillation and all byproduct diethylamine must be absent foroptimum results in the succeeding acylation stage. In using thispreferred procedure of the patent, the highest yield of thea-aminobenzylpenicillin, arnpicillin, reported to have been obtained is57 percent (cf. Example 5 of the patent).

The Irish patent also discloses the preparation of the silylatedG-aminopenicillanic acid by use of trimethylchlorosilane with a sodium,potassium, or calcium salt of fi-aminopenicillanic acid in benzene,toluene, formamide, or dimethyl formamide, in the presence of a tertiaryamine base. Such a process requires the additional preliminary step ofpreparing the salt of o-aminopenicillanic acid for use as a startingmaterial. In Example 2 of the patent, wherein this procedure is used,evaporation of the reaction mixture afforded very low yields (ZS-29percent) of disilylated fi-aminopenicillanic acid.

DESCRIPTION OF THE lNVENTlON With the foregoing disadvantages andshortcomings of the prior art in view, it is a primary object of thepresent invention to provide a practical method for preparing a-aminopenicillins of the group defined hereinafter. in high yield fromcommercially available starting materials by a process employing mildreaction conditions and short reaction times, without the necessity forthe removal of any by-products or the distillation of any solvents, andwithout the isolation of any intermediates.

In accordance with the present invention, the novel process of theinvention is useful for preparing silylated and silenated a-aminopenicillins of the group having any of the three following formulaerespectively:

wherein: when R and R are separate, R is hydrogen and R' is phenyl, andwhen R and R are joined, they complete a moiety of the group consistingof (a) a cycloalltyl ring of from four to seven carbon atoms and (b) anindane ring; R, R and R are each selected from the group consisting oflower alkyl. aryl and aralkyl; and

K. A .A. 1 n=- /s "lh w]... ('11 PM "1 (Hi i w ('u u sx- ---l 1| i t u Rwherein:

R is of the group consisting of hydrogen, alkyl, aryl and aralkyl; R isof the group consisting of halogen, alkyl, aryl and analkyl; R is of thegroup having the formula:

v n-- -t) N'llr'liCl wherein R and R have the same meaning as in FormulaI; W is of the group consisting of hydrogen, and

x siwherein R and R have the same meaning as before, and X is halogen;

m is an integer from 0 to l; n is an integer from I to about 25; p is aninteger from 0 to l and Y is of the group consisting of halogen, andgroups of the following formula:

lli.

wherein R has the same meaning as before; with the provisos that, informula ll,

1. when m is O and p is 0, n is more than I;

2. when n is more than I, the moieties A of the additional groups Brecur in random head-toward-head, headtoward-tail and tail-toward-taildisposition;

3. m and p are always equal.

in its broadest aspects, said method comprises( 1 preparing a mixture ofo-aminopenicillanic acid and a strong amine and a weak amine in anorganic solvent devoid of hydroxyl groups; (2) adding to said mixture amonoor multi-functional halosilane to form a silylated or silenatedderivative, respectively, of fi-aminopenicillanic acid; (3)incorporating in the mixture a mineral acid salt of a weak amine; andthen (4) adding to the resulting mixture containing said derivative, anorganic acid chloride hydrochloride of the group having the formula:

wherein R and R have the same meaning as in formulae I and II above.

As will appear from the Examples set forth later on herein, there may beused, as silylating agents, those ofthe monofunctional variety, such asmonohalosilanes; e.g., trimethylchlorosilane, tri-n-butylchlorosilane,diphenylmethylchlorosilane, triethylbromosilane and the like, to resultin the monomeric disilylated compounds of formula 1.;hexaalkyldisilazanes, such as hexamethyldisilazane; ortrialkylsilyldialkylamine such as trimethylsilyldiethylamine andtrimethylsi lyldimethylamine to result in the monomeric disilylated ormonosilylated compounds of formulae l. or lA., by utilizing a modifiedsequence of steps, as described hereinafter; and, as silenating agents;those of the multifunctional variety, such as dihalosilanes', e.g.,dimethyldichlorosilane, methyl hydrogen dichlorosilane,methylpropyldichlorosilane, methylphenyldichlorosilane,dimethyldibromosilane, dibutyldichlorosilane, diphenyldichlorosilane,dibenzyldichlorosilane, ethylbenzyl dibromosilane, and the like, andtrihalosilanes, for example, methyltrichlorosilane,propyltrichlorosilane, and the like to result in the silenated compoundsofformula ii.

In a preferred embodiment of the process of the invention, in step (1)above, the organic solvent devoid of hydroxyl groups is selected fromthe group consisting of methylene chloride, chloroform, tetrahydrofuran,dimethyl formamide, and acetonitrile; the molar ratio of the strongamine per mole of 6-aminopenicillanic acid is in a range of from 1.1 to2.5 moles, and that of the weak amine is in the range of 0.75 to [.25moles per mole of o-aminopenicillanic acid. In step (2), there is addedslowly to the said mixture a monofunctional halosilane until the molarratio of said silane is in the range of from I to 2 moles per mole ofn-aminopenicillanic acid, or a multi-functional halosilane until themolar ratio of said silane is in the range of 0.5 to 1.5 moles per moleof o-aminopenicillanic acid, with the molar amount of said strong aminoat least equal to the molar amount of said halosilane, to form thesilylated or silenated o-aminopenicillanic acid, respectively. Thereaction is continued at a temperature at which the reaction proceeds tocompletion in a reasonably short time. for exam ple, l to 2 hours at45C.

Other organic solvents devoid of hydroxyl groups instead of thosepreferred, may be substituted as desired. For example, the process ofthe invention may be exercised with such solvents as ethyl acetate,ethylene dichloride. benzene, toluene, ethyl ether,methylisobutylketone, and the like, or a mixture thereof which may ormay not include one or more of the preferred solvents.

In step (3), the weak amine acid addition salt is incorporated in thereaction mixture to furnish mineral acid at least in molar concentrationequivalent to the molar concentration of strong amine present in excessof that consumed in the sylylation or silenation reaction, and then instep (4), the organic acid chloride hydrochloride of formula IV above isadded slowly to provide a molar ratio of 0.75 to 1.25 per mole ofo-aminopenicillanic acid.

An alternative, and equally satisfactory means of carrying out step (3)of the method of the invention is the inactivation of the strong amine"and the formation of "weak amine and hydrochloride, in situ, by passinganhydrous hydrogen chloride into the reaction mixture containing excessweak amine".

As used herein, the "strong amines" include ammonia and those aliphaticsecondary and tertiary amines, which may be straight or branched chain,saturated or unsaturated, symmetrical or unsymmetrical, and arecharacterized by having dissociation constants in the range of from 10*to 10', or having comparable basicity, as distinguished from weakamines" which are characterized by having dissociation constants in therange offrom 10" to lO'".

As disclosed in copending U.S. application Ser. No. 67 l 35], Processfor Producing a-Amino Penicillins", C.A. Robinson and JJ. Nescio, filedOct. 2, 1967 and granted Nov. 1 l, 1969, as U.S. Pat. No. 3,478,0l8; inthe reaction of 6-APA with the strong amine in the selected solvent toform the amine salt of G-APA, for example, in the preparation ofdisilylated a-aminobenzyl penicillin hydrochloride with the ultimateview of obtaining ampicillin, results have been obtained with the use ofvarious alkyl amines as given in Table A below:

TABLE A DissociationOverall Yield Amine Constant of AmpicillinAdditionally, the use of any of trihexylamine, diisohexylamine,2,2-diethyldihexylamine, Amberlite LA-l (an aliphatic unsymmetricalbranched chain unsaturated secondary amine) and ammonia has resulted inoverall yields of ampicillin anhydrous above 65 percent. Amberlite LA-2listed in Table A above is similar to Amberlite LA-l except that theformer is saturated. Amberlite XE-204 is generally similar to AmberliteLA-2 except that it is tertiary amine.

As is also disclosed in said copending U.S. application Ser. No.67l,951, it has been found that, for obtaining the maximum yield ofultimate product, the amount of strong amine in the reaction ispreferably limited to no more than substantially one mole per mole ofthe monofunctional chlorosilane used, as shown in Table B below:

TABLE B 5% Excess Triethylamine Overall yield of Ampicillin 0 78% 10 68%l 5 58% 9% Excess Diethylamine As further described in US. applicationSer. No. 671,95], with respect to the addition oftri(lower)alkylchlorosilane to form the silylated 6-APA in step (2),theoretically, from I to 2 moles of tri(lower)alkylchlorosilane per moleof o-APA can be used to give monoor disilylated 6-APA or mixtures ofmonoand disilylated o-APA. However, in using 1.] mole of thetrimethylchlorosilane per mole of o-APA; the overall yield whenampicillin was being prepared, was 50 percent compared to a yield of 79percent when 2.0 moles of the silane per mole of 6-APA was used incomparable runs.

As appears from the foregoing, and particularly Table B; in the processfor preparing a-amino penicillins by the improved silyl route describedin said U.S. Ser. No. 671,951, it is essen tial for optimum yield to usean exact amount of strong base in the preparation of silylated 6-APAfrom trimethylchlorosilane so that none remains to interfere in thereaction with the acid chloride hydrochloride in the acylation step.Similarly, in preparing silylated 6-APA from hexamethyldisilazane or N-trimethylsilyl-dialkylamine, in accordance with the prior art methodsreferred to hereinbefore, the resulting by-product ammonia ordialkylamine, respectively, must be completely removed prior to the nextstep.

The present invention provides a unique method for the inactivation ofany strong amine which may be present as a result of incomplete usage,inaccurate measurement, or the use of an excess in exercising thegeneral method described in US. Ser. No. 67l,95l. By affording a meansof inactivating excess strong amine, the new procedure describedhereinafter allows an excess of the strong amine to be employed in thepreceding step to ensure maximum yield and subsequently to be renderedharmless. In this connection, the use of an amount of strong amine evenin excess of 2% moles per mole of 6-APA is not deleterious, if suchexcess is inactivated according to the process of this invention.However, such higher excess offers no significant advantage and hencemay preferably be avoided because of economical considerations.

More specifically, the invention comprises the inclusion of the stepofincorporating a mineral acid salt ofa weak amine in the reactionmixture prior to the addition of the organic acid chloride hydrochloridethereto. in this way, the excess strong amine is converted into itsmineral acid salt which does not interfere in subsequent reactions andthe mineral acid salt of the weak base is converted into its weak basefonn which is required in the subsequent reaction and is known to beharmless if present in excess. The amount of mineral acid salt of theweak base to be added need not be exact since any excess employed is notharmful. Thus, remarkably, neither the reagent nor any of its reactionproducts with the strong amine interfere in the subsequent reaction ofsilylated G-APA with an acid chloride hydrochloride.

With disilyl o-APA reaction mixtures prepared from 1.0 mole o-APA, 2.0moles trimethylchlorosilane, and the amounts of strong bases listedbelow, the addition of various mineral acid salts of weak amine prior totreatment with 1.0 mole of D(-phenylglycyl chloride hydrochloride hadthe beneficial effects on the yield of ampicillin, for example, asillustrated in Table C below:

Triethylamine 2. l5 Dimethylaniline HC] 0.20 82% Triethylamine 2. lDlmethylnniline 14,80, 0.l l 86% Triethylamine 2.l Pyridine HNO, 0. I486% Other weak amine hydrochloride: such as quinoline hydrochloride, andother salts such as sulfates and nitrates are also suitable asexemplified above in Table C. As noted, the mono acid salts of weakamines may be used as well as the di acid salts thereof as available anddesired. Since the mineral acid salts of the weak bases are oftenhygroscopic, they are conveniently added as solutions in methylenechloride. The strength of the solution is determined by titration.

In the addition of the organic acid chloride hydrochloride to thereaction mixture (step (4) in the presence of at least a molarequivalent of a weak tertiary amine as proton acceptor, the amount ofsaid acid chloride hydrochloride used is preferably substantiallyequimolar with the o-APA used as starting material. The acid chloridehydrochloride is preferably added portionwise under low temperatureconditions, optimally at IOC. or lower for better yields. As will alsobe apparent to those skilled in the art, the phenyl, cycloalkyl orindane ring moieties of the acylating agents may have substituentsthereon as desired, such as lower alkyl, lower alkoxy, halo, nitro, andthe like. The ultimate penicillins are obtained by hydrolysis oralcoholysis of these acylated derivatives to the penicillin per se.

Upon completion of addition of the organic acid chloride hydrochlorideto the reaction mixture, subsequent reaction at -25C. (for 15 minutes tothree hours) or at from l8-20C. (for one-half hour) has been found to beadequate. 0n the other hand, continued reaction for as long as 2l hoursat l0C.

is not seriously deleterious to the yield.

Although the weak amine base may be added for convenience in step l itcan equally be added at any time prior to the addition of the acidchloride hydrochloride in step (4). For this purpose, any weak tertiaryamine such as dimethylaniline, pyridine, quinoline or 2,6-lutidine canbe employed, whereas stronger amines such as N-ethylmorpholine aredeleterious, as exemplified in Table D below:

TABLE D Dissociation Overall yield Weak Base Constant of AmpicillinN,N-dimethylaniline 3.8 X 10"" Pyridine l.7 X HT" 79% N-elhylmorpholine5 X l0" 15% By the term weak amine, as also referred to hereinbefore, ismeant those amines having dissociation constants in the range offroml0'to 10'".

In this connection, it is noted that the use of even as much as a 50percent excess of the weak amine has no adverse effect on the yield ofthe disilylated o-APA, and hence, on the ultimate yield of thepenicillin desired.

Given below is a schematic representation of the steps l) to (4)described above as they relate to the process wherein a monofunctionalsilane; e.g., trimethylchlorosilane is used as silylating agent:

SCHEMATIC REPRESENTATION I (1) ti-A PA plus strong amino [fr-A PA-aminesalt) (fl-AIA amine salt) plus 2(Cll;)sSiCl plus strong amino disllyl[PAPA plus .2 (strong atnino-lICl) (disilyl a-amlnopeniclllin-IICI plus(weak aminelICl) wherein 6-APA represents B-aminopenicillanlc acid and Rand R have the same meaning as in Formula I In the silenation of6-aminopenicillanic acid, various proportions of diand tri-halosilanesand acid acceptors can be employed to give various novel silenatedproducts which contain a half to two silicon groups per APA group, andin which one or two of the halogen atoms of the dior tri-halosilane havereacted. For example, the reactions set forth in "SchematicRepresentations ll" which follows, wherein P= s (3 ll;

are considered to be involved:

SCI-IEMATIC REPRESENTATIONS II tlBkPA plus RR'SiXz plus base (acidacceptor) 0 It NII -P-llO lX plus buso "x (2) 6 A PA plus 2 R R'SlX:plus 2 base l? i" I ll X S iN P-UO Six plus 2 busn ll X l l R R (3)2(6-APA) plus RRSlx: plus 2 base O R 0 ll l NHz-P 0-810 P-NHzplus2base11X 6-APA plus R RSIXQ plus 2 base (5) 2(6-APAJ plus 2 RBRSIX! plus 4base R5 o R! wherein G-APA represents G-aminopenicillanic acid, and X, Rand R have the same meaning as in Formula II The products containingmore than one P" unit (i.e., wherein n I in the foregoing formulae) areconsidered to be linear or cyclic dimers, trimers and the like, orpolymers. In such cases, the repeating APA moieties of the group unitsmay be randomly disposed head-toward-tail, head-towardhead and/ortail-toward-tail in a given compound, as will be understood by thoseskilled in the art and referred to hereinbefore.

Although the products of formula ll have been prepared successfullyusing one-half to two moles of halosilane. per mole of o-APA, it ispreferred for maximum efficiency to use approximately equimolarproportions. Suitable acid acceptors include ammonia, organic amines,alkali metal carbonates, al- Italine earth metal carbonates and thelike. In general, it is preferred to use about two moles of anhydrousammonia or an amine, such as triethylamine or diethylamine, per mole ofhalosilane.

For use as solvent media in the silenation of G-APA, a wide range ofanhydrous non-hydroxylic organic solvents are suitable, includinghydrocarbons, such as benzene and toluene; chlorinated solvents such asmethylene chloride, chloroform, ethylene dichloride and chlorobenzene;ethers such as diethyl ether, dioxane and tetrahydrofuran; and otherconventional solvents such as methylisobutylketone, dimethylformamide,ethyl acetate and acetonitrilc, as already referred to hereinbefore inconnection with the silylation of 6-APA.

Among these solvents, methylene chloride, chloroform, acetonitrile, andethyl acetate are particularly useful. Since the halosilanes and thesilenated products are decomposed by moisture and other hydroxylicagents, solvents employed as reaction media must be substantiallyanhydrous and free from alcoholic impurities. Although more than 30 ml.of solvent per g. of APA has been used successfully for the silenationreaction, the use of IO ml. per g. is usually sufficient. In someinstances, however, the use of high dilution will favor intramolecularreaction and silenated derivatives of lower molecular weight, while ahigh concentration of reactants will favor intermolecular reaction andhigher molecular weight products.

In the modified procedure for preparing silylated aaminopenicillins offormula 1 and IA, wherein a hexaalkyldisilazane or atrialltylsilyldialkylamine is used as silylating agent, the method ofthe invention then comprises (a) preparing a mixture offi-aminopenicillanic acid and a hexaalkyldisilazane or atrialltylsilyldialkylamine in an organic solvent devoid of hydroxylgroups, (b) heating said mixture until silylation is complete, (c)incorporating in the mixture a weak amine, (d) adding to the resultingmixture a mineral acid salt of a weak amine to inactivate the by-productalltylamine or ammonia present. and (e) treating the mixture containingthe silylated o-aminopenicillanic acid with an organic acid chloridehydrochloride of the group having the formula IV.

In a preferred embodiment of this procedure, in step (a) above, theorganic solvent devoid of hydroxyl groups is selected from the groupconsisting of methylene chloride and chloroform; the molar amount oftrialltylsilyldialkylamine is in the range of from I to 2.2 moles permole of fi-APA or the hexaalkyldisilazane is in the range of from 0.6 to1.0 mole per mole of 6-APA. Although trimethylsilyldiethylamine andhexamethyldisilazane are preferred for reasons of economy, othersilylating agents such as trimethylsilyldimethylamine,triethylsilyldiethylamine, methyldiethyldisilazane, triethyldisilazane,etc., are suitable. With trialkylsilyldialkylamines, disilylation takesplace readily to form ultimately silylated aaminopenicillins of formulaI, while with hexaalkyldisiliazanes, monosilylation may be the principalreaction to form monosilylated a-aminopenicillins of formula [A ormixtures of monoand di-silylated products of formula I and 1A.

In step (b) above, the mixture is heated until monoor di-silylation iscomplete, for example, for l-2 hours at the reflux temperature ofmethylene chloride. When using hexaalkyldisilazanes, ammonia is evolvedduring this period. In using trialkylsilyldialltylamines, optionallysome of the dialkylamine formed in the reaction can be distilled offwith solvent during the reaction period. in step (c), the molar ratio ofweak amine is in the range of 0.75 to 1.25 moles per mole of G-APA.

In ste (d) above, the mineral acid salt of a weak amine is added to thereaction mixture to furnish mineral acid at least in molar concentrationequal to the amount of dialkylamine or ammonia formed as a by-product inthe silylation reaction and not lost by evolution or distillation duringthe reaction. in step (e), the organic acid chloride hydrochloride offormula IV is added to provide a molar concentration of from 0.75 to1.25 mole per mole of S-APA.

In the reaction of 6-APA with two molar proportions oftrimethylsilyldiethylamine in methylene chloride at reflux for 2 hours,during which time 35 percent of the by-product diethylamine wasdistilled ofi, subsequent acylation with D(- )phenylglycyl chloridehydrochloride in the presence of N,N- dimethylaniline as acid acceptorafforded a 32 percent yield of ampicillin anhydrous. In an identicalexperiment in which the residual 65 percent of the diethylamine formedin the silylation reaction was inactivated by the addition of N,N-dimethylaniline dihydrochloride prior to acylation, the yield ofampicillin was percent of theory. Even without the removal of any of thelay-product strong amine by distillation, the addition of one equivalentof N,N-dimethylaniline dihydrochloride per mole of silylating agentafforded an 82 percent yield.

in the overall procedure in which the silylated or silenated penicillinhydrochloride compounds formed in accordance with the invention are thenused to obtain the ultimate penicillin, said silylated or silenatedpenicillin hydrochloride compounds are added to water to remove thesilane groups, thereby to result in the monomeric forms of said ultimatepenicillin, regardless of whether a monoor multifunctional compound hasbeen used as silylating or silenating agent. In this step, thea-aminopenicillin hydrochloride can be completely removed from theorganic solvent reaction mixture by extraction with cold water.

In the event the ultimate penicillin to be obtained is aaminobenzylpenicillin (ampicillin), it has been found advantageous to change thechloride to an aryl sulfonic acid salt of the aminopenicillin, either byadding an appropriate sult'onic acid to the reaction mixture comprisingthe selected organic solvent and water, or to the aqueous extractsseparated as described immediately above. In this connection a 25percent excess of the sulfonic acid has been used to advantage inpreparing the corresponding salt of ampicillin.

The aryl sulfonic salt of the a-aminobenzyl penicillin may then beconverted to the penicillin per se by reaction with a base such astriethylamine or diethylamine in approximately 85 percent isopropanol.1n the case of ampicillin specifically, the sulfonic acid salt, wet withwater and ethyl acetate, may be added to isopropanol containing a molarequivalent of triethylamine at 7$-80C., whereby the anhydrous form ofampicillin described and claimed in U.S. Pat. No. 3,144,445 is formedand collected by filtration from the hot mixture.

Alternatively, the corresponding penicillin may be obtained, but inhydrated form, by raising the pH of the aqueous reaction mixturecontaining the hydrochloride salt of said penicillin to the iso-electricpoint.

The subsequent steps in the production of the a-amino penicillin per sefrom the silylated amino penicillin hydrochloride is represented inSchematic Representation 11]" below with reference specifically to theproduction of ampicillin wherein a monofunctional chlorosilane is usedas silylating agent:

SCHEMATIC REPRESENTATION III (5) (Disilyl ampicilliuJICl) plus 1120(Ampiclllln 1101) plus (CllahSIOSKClh);

6] gAmpiclllln HCI) plus plus NaOH (ampicillin anhydrous) plus It willagain be understood that, instead of the disilylated ampicillin HCIgiven in the foregoing Schematic Representation 111", a silenatedcompound of formula 11 may be used The following examples areillustrative of the invention and should not be considered asnecessarily limitative thereof:

EXAMPLE 1 PREPARATION OF ANHYDROUS AMPICILLIN A. To a mixture of 43.2 g.(0.20 mole) of o-aminopenicillanic acid and 450 ml. of methylenechloride in a 1 L. 3-nec1t flask fitted with stirrer, thermometer,nitrogen inlet tube, and reflux condenser with drying tube, 50.5 g.(0.50 mole) of triethylamine and 26.7 g. (0.22 mole) ofN,N-dimethylaniline were added. After refluxing for lhour, the turbidsolution was cooled and 43.4 g. (0.40 mole) of trimethylchlorosilane wasadded dropwise over 7 minutes at 12-l 5C.

B. The mixture was allowed to reflux for 45 minutes and cooled undernitrogen to 20C. Then ml. of a 0.70 molar solution of dimethylanilinedihydrochloride in methylene chloride was added. After cooling themixture, 41.3 g. (0.20 mole) of D(-)phenylg1ycyl chloride hydrochloridewas added portionwise over 20 minutes at -10"C. The reaction mixture wasallowed to stir at -l0C. for one-half hour and then warmed to 10C. overone-half hour.

C. The reaction mixture was poured into 900 ml. of cold water withstirring and the aqueous layer decanted. The methylene chloride layerwas re-extracted twice with 900 ml. of cold water, each time adjustingthe mixture to pH 1.8-2.0 with dilute hydrochloric acid.

D. After clarifying the aqueous mixture by filtration, ml. of ethylacetate was added,fo1lowed by the dropwise addition of a solution ofB-naphthalene sulfonic acid containing 52 g. (0.25 mole) of active agentand the concurrent addition of dilute sodium hydroxide to maintain a pHof 1.5-1.8. After stirring overnight at 2-SC, the white, crystallinenaphthalene sulfonic acid salt of ampicillin was collected byfiltration, washed thoroughly with cold water and finally with ethylactate. A sample dried in a vacuum oven at 50-60C. showed the wet filtercake 177 g.) to contain 58.5 percent solids.

E. The wet filter cake was added to a solution of 215 ml. of isopropanoland 19.5 g. of triethylamine at 75-80C. with rapid stirring and thenallowed to stir for 15 minutes. The white, crystalline ampicillinanhydrous was fiitered from the hot reaction mixture, washed with 85percent aqueous isopropanol, and dried at 45C; yield 58 g. or 83 percentof theory from o-aminopenicillanic acid; iodometric assay, 969 mcg. permg.; bioassay, 973 meg/mg.

EXAMPLE 2 The procedure of Example 1 was followed except that theaddition if dimethylaniline dihydrochloride was omitted; yield ofampicillin anhydrous, 40.5 g. or 58 percent of theory.

EXAMPLE 3 A. To 43.2 g. of o-APA and 425 ml. of methylene chloride in a1 L. B-neclt flask fitted with stirrer, thermometer, nitrogen inlet, anddrying tube, 43.4 g. (0.43 mole) of triethylamine of 26.7 g. ofN,N-dimethylaniline are added. The mixture is cooled and 43.4 g. oftrimethylchlorosilane is added dropwise at l0-l5C.

B. After refluxing for one hour, the mixture is cooled to 20C, and 25ml. of a 1.6 molar solution of N,N- dimethylaniline mono hydrochloridein methylene chloride is added. D(-)phenylglycyl chloride HCI (41.3 g.)is then added portionwise over 20 minutes at l0C.

C. Completion of reaction, isolation of an aryl sulfonic acid salt andconversion to ampicillin anhydrous as described in Example 1, C-E,affords 57.3 or 82 percent of theory based on 6-APA.Bioassay, 947mcgJmg.

EXAMPLE 4 A. To 173 g. (0.80 mole) of o-APA and 1,700 ml. of methylenechloride in a 5 L. 3-neck flask fitted with stirrer thermometer,nitrogen inlet, and drying tube, g. (1.68 moles) of triethylamine and116 g. (0.96 mole) of N,N- dimethylaniline are added. After cooling themixture, 174 g.

( 1.6 moles) of trimethylchlorosilane is added slowly at l2-15 C EXAMPLE5 The process of Example 4 was followed, except that 89 ml. of a 1.8Nsolution of dimethylaniline '2HC1 was substituted for the anhydrous HClThe yield of anhydrous ampicillin was 238 g. or 85 percent of from 6APA;iodometric assay, 992 meg/mg.

EXAMPLE 6 A. To a mixture of 43.2 g. (0.20 mole) of 6-aminopenicillanicacid and 450 ml. of methylene chloride in a 1 L. 3-neck flask fittedwith stirrer, thermometer, nitrogen inlet tube, and reflux condenserwith drying tube, 40.5 g. (0.40 mole) of triethylamine and 26.7 g. (0.22mole) of N,N-dimethy1aniline were added. The solution was cooled and43.4 g. (0.40 mole) of trimethylchlorosilane was added dropwise over 7minutes at l2-15C.

B. The mixture was allowed to reflux for one hour and cooled undernitrogen to 20C. Then 6 ml. ofa 3.35 N solution of dimethylanilinedihydrochloride in methylene chloride was added. After cooling themixture, 41.3 g. (0.20 mole) of D(- )phenylglycycl chloridehydrochloride was added portionwise over 20 minutes at l0C. The reactionmixture was allowed to stir at l0C. for one-half hour and then warmed to10C. over one-half hour.

C. The reaction mixture was poured into 1200 ml. of cold water and thenthe procedure of Example 1, D and E was followed. Anhydrous ampicillinwas obtained in 86 percent yield based on 6-APA; bioassay,973 meg/mg.

EXAMPLE 7 Utilizing the procedure of Example 6, the following organicsolvents were substituted for methylene chloride to obtain yields ofanhydrous ampicillin as given in Table E below:

TABLE E Yield of Solvent Anhydrous Ampicillin Acetonitrile 75%Chlorol'orm 80% Tetrahydrofuran 76% Ethyl Acetate 53% DimethylFormamitle 63% EXAMPLE 8 PREPARATION OF l-AMlNOCYCLOl-IEXANE PENlClLLlNDIHYDRATE minutes. Reaction was completed by warming to 20C. andstirring for 1 hour.

The mixture was poured into 400 ml. of ice-water with stirring and thetwo-phase mixture clarified by filtration. After separating layers, themethylene chloride layer was extracted with 50 ml. of water. lsopropylalcohol (400 ml.) was added to the combined aqueous layers, and the pHadjusted to 5.4 with dilute sodium hydroxide. After stirring for 16hours at 20C., the crystalline product was collected by filtration,washed with acetone, and dried at 45C. The yield of 6-(l-aminocyclohexanecarboxamido) penicillanic acid dihydrate was 77.0 g.or 82 percent of theory.

Following the same procedure except omitting the addition ofdimethylaniline dihydrochloride, the yield was 71.4 g. or 76 percent oftheory.

EXAMPLE 9 Employing the procedure of Example 8, but substituting for thel amino-l-cyclohexane carboxylic acid chloride hydrochloride usedtherein; the acid chloride hydrochlorides given in Table F below, thecorresponding penicillins, which are disclosed per se in US. Pat. No.3,194,802, are obtained.

TABLE F Carboxylic Acid Chloride Hydrochloride 1-aminol cyclobutanel-aminol cyclopentane 1-amino 1-cycloheptane EXAMPLE l0 PREPARATION OFZ-AMINOINDANE PENlClLLlN To 540 g. of 6-APA and 530 ml. of methylenechloride, 53.2 g. (0.525 mole) of triethylamine and 33.9 g. (0.28 mole)of N,N-dimethylaniline were added. The mixture was cooled under drynitrogen and 54.3 g. of trimethylchlorosilane was added over 10 minutes.

After heating at reflux for one hour with stirring, the mixture wascooled and 15 ml. of a 1.6 molar solution of N,N- dimethylanilinedihydrochloride in methylene chloride was added. The mixture wasfiltered under dry nitrogen and the filter cake washed twice withmethylene chloride. Then, 61.0 g. of 2-amino-2-carboxyindane acidchloride hydrochloride was added portionwise at 0C. over 20 minutes.After an additional 15 minutes at 0C., the solution was warmed to 20 C.and stirred for 15 minutes at 20C.

The mixture was poured into 650 ml. of cold water with stirring,clarified by filtration, and neutralized to pH 5.8 with dilute alkali.After stirring for 16 hours at 0-5C., the product was collected byfiltration, washed with water and acetone, and dried at 45C. The yieldof 6-( Z-amino-Z-indanecarboxyamido) penicillanic acid was 82.0 g. or 87percent of theory; purity by iodometric assay, 98 percent.

EXAMPLE 1 1 Following the procedure of Example 6, 108 g. (0.40 mole) oftri-isohexylamine was substituted for triethylamine. The yield ofampicillin anhydrous was 77 percent of theory; iodometric assay, 986mcg. per mg.

EXAMPLE 12 Following the procedure of Example 6, 32.1 g. (0.44 mole) ofdiethylamine was substituted for triethylamine and 9.2 g. of pyridinehydrochloride in methylene chloride was substituted for thedimethylaniline dihydrochloride; yield, 78 percent of theory; bioassay,970 mcg. per mg.

EXAMPLE l3 Utilizing the procedure of Example 6, dimethyldichlorosilane(25.8 g.; 0.20 mole) was substituted for the trimethylchlorosilane, theamount of triethylamine was increased to 46.5 g., and 13 ml. of 1.6molar solution of dimethylaniline dihydrochloride was used. The yield ofampicillin anhydrous was 58.0 g. or 83 percent of theory; bioassay, 953cg. per mg.

Following the same procedure except omitting the addition ofN,N-dimethylaniline dihydrochloride, the yield was 70 percent oftheory.

EXAMPLE 14 To 580 ml. of methylene chloride containing 0.43 mole ofanhydrous ammonia, 43.2 g. of 6-APA and 26.7 g. of N,N- dimethylanilinewere added followed by the dropwise addition of 25.8 g. ofdimethyldichlorosilane at 12C. After refluxing gently for l hour, themixture was cooled to 10C. under dry nitrogen and 13 ml. of 1.6 molarsolution of dimethylaniline dihydrochloride in methylene chloride wasadded to inactivate excess ammonia.

At C., 41.9 g. of D(-)phenylglycycl chloride hydrochloride was addedportionwise over 20 minutes. After warming to 10C. and stirring for anadditional 15 minutes, the mixture was poured into 1,200 ml. ofice-water and then the procedure of Example 1, D and E, was followed.The yield of anhydrous ampicillin was 56.0 g. or 80 percent oftheory.

EXAMPLE l Methyl hydrogen dichlorosilane (23.0 g.; 0.20 mole) was addeddropwise at l3-l5C. to a mixture of 43.2 g. of 6-APA, 44.5 g. oftriethylamine, and 450 ml. of dry methylene chloride with stirring.After heating at 38C. for 30 minutes, the mixture was cooled and 23 ml.of a 1.3 molar solution of dimethylaniline dihydrochloride in methylenechloride and 26.7 g. of N,N-dimethylaniline were added.

Then, 41.3 g. of D(-)phenylglycyl chloride hydrochloride was addedportionwise at 0C. and the mixture was stirred for 1% hours at 0-10C.After pouring the entire mixture into 1,200 ml. of cold water andstirring at C. for minutes, a small amount of insoluble matter wasremoved by filtration. Treatment of the two-phase mixture with ethylacetate and then with fl-naphthalenesulfonic acid as described inExample 1 D afforded 77.5 g. (dry basis) of the B-naphthalenesulfonicacid salt of ampicillin or 70 percent of theory.

Following an identical procedure except omitting the addition of thedimethylaniline dihydrochloride, the yield was 63.5 g. or 57 percent oftheory.

EXAMPLE l6 PREPARATION OF AMPlClLLlN TRll-IYDRATE In a 1 liter 3-neckflask fitted with stirrer, thermometer, and reflux condenser withsoda-lime drying tube, a mixture of 43.2 g. of 6-APA, 25.8 g. (0.16mole) of hexamethyldisilazane, and 435 ml. of methylene chloride washeated at 40-4lC. for two hours. After allowing the turbid solution tocool, 29.1 g. of N,N-dimethylaniline and 8 ml. of a 1.3 molar solutionof dimethylaniline dihydrochloride in methylene chloride were added.Then, 42.0 g. of D(-)phenylgylcyl chloride hydrochloride was added inportions at 0C., and reaction was completed by warming slowly to 10C.and stirring 15 minutes at 10C.

The mixture was poured into 750 ml. of ice-water with stirring,filtered, and the methylene chloride layer discarded. After adjustingthe aqueous phase to pH 5.0 with 79 ml. of5 N sodium hydroxide, themixture was allowed to stir overnight at 0-5C. The white, crystallineproduct was collected by filtration, washed with isopropanol-water, anddried at 45C. The yield of ampicillin trihydrate was 65.0 g. or 80percent of theory; purity by iodometric assay, 100 percent.

In an identical experiment in which the addition of N,N- dimethylanilinedihydrochloride was omitted, the yield was 22.7 g. or 28 percent oftheory.

EXAMPLE 1? A mixture of 46.4 g. (0.214 mole) of 6-APA, 24.3 g. (0.15mole) of hexamethyldisilazane, and 420 ml. of methylene chloride washeated under reflux for 3 hours with stirring allowing ammonia toescape. After cooling and clarifying the solution by pressurefiltration, 26.7 g. of N,N-dimethylaniline was added, and 0.4 g. ofanhydrous hydrogen chloride was passed into the mixture.

At 0-5C., 42.l g. of D(-)phenylgylcyl chloride hydrochloride was addedin portions and then the mixture was warmed slowly and allowed to stirat 10C. for one-half hour. After pouring the mixture into 1,200 ml. ofice-water, filtering, and discarding the methylene chloride phase, theprocedure of Example I, D and E, was followed. The yield of ampicillinanhydrous was 60.8 g. or 81 percent of theory based on 6-APA.

EXAMPLE 18 To 43.2 g. (0.20 mole) of 6-aminopenicillanic acid and 425ml. of methylene chloride in a dry 1 liter 3-neck flask fitted withstirrer, thermometer, and nitrogen inlet, 58.2 g. (0.40 mole) oftrimethylsilyldiethylamine was added. After stirring the mixture underreflux (43C.) for 1 hour, methylene chloride was allowed to distill offuntil 300 ml. of distillate had been collected in 1 hour. Titration ofthe distillate indicated that 0.14 mole of diethylamine had been removedin the distillation. The pale yellow reaction mixture was cooled,diluted with 300 ml. of methylene chloride, and 31.5 g. of N,N-dimethylaniline added.

After adding ml. of a L55 molar solution of N,N- dimethylanilinedihydrochloride in methylene chloride, 41.3 g. of D(-)phenylglycylchloride hydrochloride was added portionwise over 20 minutes at 0C. Themixture was allowed to stir at 0C. for 15 minutes, then at lOC. for 15minutes, and finally was poured into 1,200 mi. of ice-cold water withstirring. After clarifying the two-phase mixture by filtration, 150 ml.of ethyl acetate was added followed by B-naphthalenesulfonic acidanalogous to the procedure of Example 1, D and E. The yield ofampicillin anhydrous was 55.7 g. of 80 percent of theory; iodometricassay, 986 mcg. per mg.; bioassay, 927 mcg. per mg.

Following the same procedure except omitting the addition ofN,N-dimethylaniline dihydrochloride, the yield was 32 per cent oftheory.

EXAMPLE 19 The procedure of Example 18 was followed except thatmethylene chloride was distilled off until the temperature reached 49C.The distillate (350 ml.) contained 0.17 mole of diethylamine bytitration. In this experiment, the excess diethylamine was inactivatedby adding pyridine hydrochloride in place of dimethylanilinedihydrochloride. The yield of ampicillin anhydrous was 50.9 g. or 73percent of theory; bioassay, 983 mcg. per mg.

EXAMPLE 20 The procedure of Example 18 was followed except that themixture was allowed to reflux for two hours, no diethylamine was removedby distillation, and ml. of a 1.6 molar solution of N,N-dimethylanilinedihydrochloride in methylene chloride was used. The over-all yield ofampicillin anhydrous was 57.5 g. or 82 percent of theory; bioassay, 987mcg. per mg.

EXAMPLE 21 Utilizing the procedure of Example 6, tri-n-butylchlorosilane(94 g.; 0.40 mole) was substituted for trimethylchlorosilane, and theamount of triethylamine was increased to 42.6 g. Sixteen ml. of a 2.6 Nsolution of dimethylaniline dihydrochloride in methylene chloride wasadded prior to the phenylglycyl chloride hydrochloride which was addedat C. and allowed to react at l-20C. for 30 minutes. The yield of theB-naphthalenesulfonic acid salt of ampicillin was 87 percent of theory.

Following the above procedure with tri-ethylbromosilane (78 g.) assilylating agent, the yield of the intermediate salt of ampicillin was92 percent of theory.

The use of diphenylmethylchlorosilane (93 g.) in an analogous procedureafforded an 85 percent yield of the B- naphthalene-sulfonic acid salt ofampicillin.

EXAMPLE 22 Methylpropyldichlorosilane l5.7 g; 0.10 mole) was addeddropwise at -l 5C. to a mixture of 2 l .6 g. of b-APA, 21.2 g. oftriethylamine, 13.4 g. of N,N-dimethylaniline, and 230 ml. of methylenechloride with stirring. After heating at reflux for 2 hours, the mixturewas cooled and 6 ml. ofa 2.6 N solu' tion of dimethylanilinedihydrochloride in methylene chloride was added.

After adding 213 g. of D(-)phenylglycyl chloride hydrochlorideportionwise at 0C., the mixture was allowed to stir at 10C. for 1%hours. The pale yellow reaction mixture was poured into 600 ml. ofice-water, the mixture clarified by filtration and the layers separated.Treatment of the aqueous layer with fl-naphthalenesulfonic acid asdescribed in Example l D afforded the B-naphthalenesulfonic acid salt ofampicillin, 49.6 g. or 89 percent of theory.

EXAMPLE 23 Following the procedure of Example 22,methylphenyldichlorosilane l 9.1 g.; 0.10 mole) was substituted formethylpropyldichlorosilane and 8 ml. of 2.6 N dimethylanilinedihydrochloride was used for inactivation of the excess amine. The yieldof the fi-naphthalenesulfonic acid salt of ampicillin was 45 g. or 81percent oftheory.

I claim:

1. A method of preparing a silylated, or silenated, acid chloride saltof a penicillin of the group having one of the three following formulas1., IA., and II., respectively:

I. wherein, when R and R are separate, R is hydrogen and R is phenyl,and when R and R are joined, they complete a ring selected from thegroup consisting of cycloalkyl of from four to seven carbon atoms, andindane; and R. R and R are each selected from the group consisting oflower alkyl and phenyl. lower alkylphenyl and benzyl;

wherein, R, R, R R and R have the same meaning as in formula l.; and

A 1 It s lwlm (ll1 i I! wherein:

R is of the group consisting of hydrogen, lower alkyl, phenyl, loweralkylphenyl and benzyl; R is of the group consisting of halo, loweralkyl, phenyl,

lower alkylphenyl and benzyl; R" is of the group consisting of thosehaving the formula:

RIJ L lliIlrllCl llA.

wherein R and R have the same meaning as in formula I above; W is of thegroup consisting of hydrogen and llli.

wherein R and R have the same meaning as in formula IL,

and X is halogen;

m is an integer from O to l;

n is an integer from I to about 25;

p is an integer from 0 to I;

Y is of the group consisting of halogen and groups of the followingformula:

III.

wherein R" has the same meaning as before; with the provisos that, informula ll.,

1. when m is 0 andpis 0, n is more than I;

2. when n is more than 1, the moieties A of the additional groups Brecur in random head-toward-head, headtoward-tail and tail-toward-taildisposition; and

3. m is always equal to p.

which method comprises following one of the two sequences ofsteps (A) or(B) given below:

l. preparing a mixture of -aminopenicillanic acid, a strong amine, and aweak amine, in an organic solvent devoid of hydroxyl groups;

2. incorporating in said mixture a monoor multifunctional halosilane;

3. also incorporating in said mixture, a mineral acid salt of a weakamine; and thereafter 4. adding to the resulting mixture, an organicacid chloride hydrochloride of the group having the formula:

f H ino el Nth-11c:

wherein R and R have the same meaning as in formula 1 above; andwherein:

in l. the molar ratio of said strong amine per mole of 6-aminopenicillanic acid is in the range of from 1.1 to about 2.5 moles;and that of said weak amine is in the range of from 0.75 to [.25 molesper mole of 6- aminopenicillanic acid;

in 2. said halosilane is added to said mixture in amount so that themolar ratio of said halosilane, if mono-functional, is in the range offrom about 1 to about 2 moles per mole of fi-aminopenicillanic acid,and, if multifunctional, is in the range of from about is to about 2moles, with the molar amount of said strong amine, in either case, atleast equal to the molar amount of said halosilane;

in 3. said mineral acid salt of a weak amine is incorporated in anamount to furnish mineral acid at least in molar concentrationequivalent to the molar concentration of said strong amine present inexcess of that consumed in the silylation or silenation reaction; and

in 4. said organic acid chloride hydrochloride is added in amount toprovide a molar ratio of 0.75 to L25 per mole of o-aminopenicillanicacid;

with the provisos that:

a. when the halosilane selected is monofunctional, a disilylated acidchloride salt of a penicillin of formula I. is obtained, and

b. when the halosilane selected is multifunctional, a silenated acidchloride salt of a penicillin of formula I]. is obtained; or

. preparing a mixture of o-aminopenicillanic acid and a silylating agentselected from the group consisting of trialkylsilyldialkylamines andhexaalkyldisilazanes, in an organic solvent devoid of hydroxyl groups;

heating said mixture until silylation is complete;

. incorporating in the mixture, a weak amine;

. adding to the resulting mixture, a mineral acid salt of a weak amine;and

5. treating the final mixture with an organic acid chloridehydrochloride of the group having the formula IV. above; and

wherein:

in 1., when a trialkylsilyldialkylamine is selected, it is added inamount so that the molar ratio thereof is in the range of from about Ito about 2.2 moles per mole of 6- aminopenicillanic acid; and when ahexaalkyldisilazane is selected, it is added in amount so that the molarratio thereof is in the range from about 0.6 to about l.0 mole per moleof fi-aminopenicillanic acid; and

in 3., the molar ratio of weak amine incorporated in the mixture is inthe range of from about 0.75 to L25 moles per mole ofG-aminopenicillanic acid;

in 4., said mineral acid salt of a weak amine is incorporated in anamount to furnish mineral acid in at least molar concentration toinactivate the by-product alkylamine or ammonia furnished in thesilylation reaction; and

in 5., said organic acid chloride hydrochloride is added in amount toprovide a molar ratio of 0.75 to 1.25 moles per mole offi-aminopenicillanic acid;

with the provisos that:

a. when the silylating agent selected is a trialkylsilyldialkylamine, adisilylated acid chloride salt of a penicillin of formula 1. above isobtained; and

b. when the silylating agent selected is a hexaalkyldis ilazane, thesilylated acid chloride salt of a penicillin obtained is selected fromthe group consisting of those having the formulas l. and IA., andmixtures thereof.

2. A method of preparing a silylated or silenated, acid chloride salt ofa penicillin, as defined in claim 1, wherein: the organic solvent devoidof hydroxyl groups is selected from the group consisting of methylenechloride, chloroform, tetrahydrofuran, dimethyl formamide, andacetonitrile.

3. A method of preparing a silylated or silenated acid chloride salt ofa penicillin, as defined in claim 2, wherein:

the strong amine selected or furnished, is of the group consisting ofammonia, diethylamine, triethylamine,

dioctylamine, and 2,2-diethyl-dihexylamine.

4. A method of preparing a silylated or silenated acid chloride salt ofa penicillin, as defined in claim 3, wherein:

the weak amine is selected from the group consisting ofN,N-dimethylanillne, quinoline, and pyridine.

5. A method of preparing a silylated acid chloride salt of a penicillinof formula 1.. as defined in claim 4, wherein:

the silylating agent is trimethylchlorosilane.

6. A method of preparing a silenated acid chloride salt of a penicillinof formula II., as defined in claim 4, wherein:

the silylating agent is dimethyldichlorosilane.

7. A method of preparing a silylated acid chloride salt of a penicillinof formula l., as defined in claim 2, wherein:

bu ld the silylating agent is timethylsilyldi-ethylamine.

8. A method of preparing a silylated acid chloride salt of a penicillinof formula I. or 1A., or mixtures thereof, as defined in claim 2,wherein:

the silylating agent is hexamethyldisilazane.

9. A method of preparing a silylated or silenated, acid chloride salt ofa penicillin, as defined in claim 4, wherein:

the acid salt of a weak amine is N,N-dimethylaniline hydrochloride.

10. A method of preparing a silylated or silenated, acid chloride saltof a penicillin, as defined in claim 4, wherein:

any excess strong amine is inactivated and the weak amine hydrochlorideis formed in situ, by passing anhydrous hydrogen chloride into themixture containing the strong amine and the weak amine.

ll. A method of preparing a silylated or silenated, acid chloride saltof a penicillin, as defined in claim 4, wherein:

the organic acid chloride hydrochloride is selected from the groupconsisting of D(-)-phenylglycyl chloride hydrochloride,l-amino-l-cyclohexane carboxylic acid chloride hydrochloride and2-amino-2-carboxyindane acid chloride hydrochloride.

l2. A method of preparing a silylated or silenated derivative ofo-aminopenicillanic acid in a reaction medium suitable for use insubsequent procedures for preparing penicillin derivatives, which methodcomprises:

preparing a mixture of 6-aminopenicillanic acid, a strong amine, a weakamine and a monoor multifunctional halosilane in an organic solventdevoid of hydroxyl groups, in molar ratios of in excess of 2 moles ofstrong amine, from 0.75 to l.25 moles of a weak amine, and from about 1to about 2 moles of said halosilane per mole of 6aminopenicillanic acidwhen a monofunctional halosilane is used, and from about V4 to about 2moles of said halosilane per mole of o-aminopenicillanic acid when amultifunctional halosilane is used; then incorporating therein mineralacid salt of a weak amine in amount to provide a molar concentrationthereof at least equivalent to the excess of that consumed in thesilylation or silenation reactions.

13. A method of preparing a silylated derivative of 6- aminopenicillanicacid, as defined in claim l2, wherein:

a monofunctional halosilane is used in amount to afford from about 1.75to 2.0 moles thereof per mole of 6- aminopenicillanic acid.

14. A method of preparing a silylated derivative of 6 aminopenicillanicacid, as defined in claim 12, wherein:

a multifunctional halosilane is used in amount to afford from about 0.8to about 12 moles thereof per mole of 6- aminopenicillanic acid.

IS. A method of preparing a derivative of 6-aminopenicillanic acid in areaction medium suitable for use in subsequent procedures for preparingpenicillins which method comprises:

preparing a mixture of iS-aminopenicillanic acid and a silylating agentselected from the group consisting of trialkylsilyldialkylamines andhexaalkyldisilazanes, in an organic solvent devoid of hydroxyl groups,so that, when a trialkylsilyldialkylamine is selected, it is present inamount to provide a molar ratio thereof in the range from about I toabout 2.2 moles per mole of 6-aminopenicillanic acid, and when ahexaalkyldisilazane is selected, it is present in amount to provide amolar ratio thereof in the range from about 0.6 to about l.0 mole permole of 6- aminopenicillanic acid, heating said mixture until silylationis complete, incorporating in the mixture, a weak amine, in amount toprovide a molar ratio of from about 0.75 to 1.25 moles thereof per moleof 6-aminopenicil lanic acid, and then incorporating into the resultingmixture a mineral acid salt of a weak amine in at least molarconcentration to inactivate the byproduct alkylamine or ammoniafurnished in the silylation reaction.

16. A method of preparing a silylated derivative of 6- aminopenicillanicacid, as defined in claim 15, wherein:

the silylating agent is trimethylsilyldiethylamine.

17. A method of preparing a silylated derivative of 6- the silylatingagent is hexamethyldisilazane. aminopenicillanic acid,asdefincd in claim15, wherein: n: 1i i- I

2. A method of preparing a silylated or silenated, acid chloride salt ofa penicillin, as defined in claim 1, wherein: the organic solvent devoidof hydroxyl groups is selected from the group consisting of methylenechloride, chloroform, tetrahydrofuran, dimethyl formamide, andacetonitrile.
 2. when n is more than 1, the moieties A of the additionalgroups B recur in random head-toward-head, head-toward-tail andtail-toward-tail disposition; and
 2. incorporating in said mixture amono- or multifunctional halosilane;
 2. heating said mixture untilsilylation is complete;
 3. incorporating in the mixture, a weak amine;3. also incorporating in said mixture, a mineral acid salt of a weakamine; and thereafter
 3. m is always equal to p. which method comprisesfollowing one of the two sequences of steps (A) or (B) given below: (A)3. A method of preparing a silylated or silenated acid chloride salt ofa penicillin, as defined in claim 2, wherein: the strong amine selectedor furnished, is of the group consisting of ammonia, diethylamine,triethylamine, dioctylamine, and 2,2''-diethyl-dihexylamine.
 4. A methodof preparing a silylated or silenated acid chloride salt of apenicillin, as defined in claim 3, wherein: the weak amine is selectedfrom the group consisting of N,N-dimethylaniline, quinoline, andpyridine.
 4. adding to the resulting mixture, an organic acid chloridehydrochloride of the group having the formula: wherein R and R1 have thesame meaning as in formula I above; and wherein: in
 1. the molar ratioof said strong amine per mole of 6-aminopenicillanic acid is in therange of from 1.1 to about 2.5 moles; and that of said weak amine is inthe range of from 0.75 to 1.25 moles per mole of 6-aminopenicillanicacid; in
 2. said halosilane is added to said mixture in amount so thatthe molar ratio of said halosilane, if mono-functional, is in the rangeof from about 1 to about 2 moles per mole of 6-aminopenicillanic acid,and, if multifunctional, is in the range of from about 1/2 to about 2moles, with the molar amount of said strong amine, in either case, atleast equal to the molar amount of said halosilane; in
 3. said mineralacid salt of a weak amine is incorporated in an amount to furnishmineral acid at least in molar concentration equivalent to the molarconcentration of said strong amine present in excess of that consumed inthe silylation or silenation reaction; and in
 4. said organic acidchloride hydrochloride is added in amount to provide a molar ratio of0.75 to 1.25 per mole of 6-aminopenicillanic acid; with the provisosthat: a. when the halosilane selected is monofunctional, a disilylatedacid chloride salt of a penicillin of formula I. is obtained, and b.when the halosilane selected is multifunctional, a silenated acidchloride salt of a penicillin of formula II. is obtained; or (B) 4.adding to the resulting mixture, a mineral acid salt of a weak amine;and
 5. treating the final mixture with an organic acid chloridehydrochloride of the group having the formula IV. above; and wherein: in1., when a trialkylsilyldialkylamine is selected, it is added in amountso that the molar ratio thereof is in the range of from about 1 to about2.2 moles per mole of 6-aminopenicillanic acid; and when ahexaalkyldisilazane is selected, it is added in amount so that the molarratio thereof is in the range from about 0.6 to about 1.0 mole per moleof 6-aminopenicillanic acid; and in 3., the molar ratio of weak amineincorporated in the mixture is in the range of from about 0.75 to 1.25moles per mole of 6-aminopenicillanic acid; in 4., said mineral acidsalt of a weak amine is incorporated in an amount to furnish mineralacid in at least molar concentration to inactivate the by-productalkylamine or ammonia furnished in the silylation reaction; and in 5.,said organic acid chloride hydrochloride is added in amount to provide amolar ratio of 0.75 to 1.25 moles per mole of 6-aminopenicillanic acid;with the provisos that: a. when the silylating agent selected is atrialkylsilyldialkylamine, a disilylated acid chloride salt of apenicillin of formula I. above is obtained; and b. when the silylatingagent selected Is a hexaalkyldisilazane, the silylated acid chloridesalt of a penicillin obtained is selected from the group consisting ofthose having the formulas I. and IA., and mixtures thereof.
 5. A methodof preparing a silylated acid chloride salt of a penicillin of formulaI., as defined in claim 4, wherein: the silylating agent istrimethylchlorosilane.
 6. A method of preparing a silenated acidchloride salt of a penicillin of formula II., as defined in claim 4,wherein: the silylating agent is dimethyldichlorosilane.
 7. A method ofpreparing a silylated acid chloride salt of a penicillin of formula I.,as defined in claim 2, wherein: the silylating agent istimethylsilyldi-ethylamine.
 8. A method of preparing a silylated acidchloride salt of a penicillin of formula I. or IA., or mixtures thereof,as defined in claim 2, wherein: the silylating agent ishexamethyldisilazane.
 9. A method of preparing a silylated or silenated,acid chloride salt of a penicillin, as defined in claim 4, wherein: theacid salt of a weak amine is N,N-dimethylaniline hydrochloride.
 10. Amethod of preparing a silylated or silenated, acid chloride salt of apenicillin, as defined in claim 4, wherein: any excess strong amine isinactivated and the weak amine hydrochloride is formed in situ, bypassing anhydrous hydrogen chloride into the mixture containing thestrong amine and the weak amine.
 11. A method of preparing a silylatedor silenated, acid chloride salt of a penicillin, as defined in claim 4,wherein: the organic acid chloride hydrochloride is selected from thegroup consisting of D(-)-phenylglycyl chloride hydrochloride,1-amino-1-cyclohexane carboxylic acid chloride hydrochloride and2-amino-2-carboxyindane acid chloride hydrochloride.
 12. A method ofpreparing a silylated or silenated derivative of 6-aminopenicillanicacid in a reaction medium suitable for use in subsequent procedures forpreparing penicillin derivatives, which method comprises: preparing amixture of 6-aminopenicillanic acid, a strong amine, a weak amine and amono- or multifunctional halosilane in an organic solvent devoid ofhydroxyl groups, in molar ratios of in excess of 2 moles of strongamine, from 0.75 to 1.25 moles of a weak amine, and from about 1 toabout 2 moles of said halosilane per mole of 6-aminopenicillanic acidwhen a monofunctional halosilane is used, and from about 1/2 to about 2moles of said halosilane per mole of 6-aminopenicillanic acid when amultifunctional halosilane is used; then incorporating therein mineralacid salt of a weak amine in amount to provide a molar concentrationthereof at least equivalent to the excess of that consumed in thesilylation or silenation reactions.
 13. A method of preparing asilylated derivative of 6-aminopenicillanic acid, as defined in claim12, wherein: a monofunctional halosilane is used in amount to affordfrom about 1.75 to 2.0 moles thereof per mole of 6-aminopenicillanicacid.
 14. A method of preparing a silylated derivative of6-aminopenicillanic acid, as defined in claim 12, wherein: amultifunctional halosilane is used in amount to afford from about 0.8 toabout 1.2 moles thereof per mole of 6-aminopenicillanic acid.
 15. Amethod of preparing a derivative of 6-aminopenicillanic acid in areaction medium suitable for use in subsequent procedures for preparingpenicillins which method comprises: preparing a mixture of6-aminopenicillanic acid and a silylating agent selected from the groupconsisting of trialkylsilyldialkylamines and hexaalkyldisilazanes, in anorganic solvent devoid of hydroxyl groups, so that, when atrialkylsilyldialkylamine is selected, it is present in amount toprovide a molar ratio thereof in the range from about 1 to about 2.2moles per mole of 6-aminopenicillanic acid, and when ahexaalkyldisilazane is selected, it is present in amount to provide amolar ratio thereof in the range from about 0.6 to about 1.0 mole permole of 6-aminopenicillanic acid, heating said mixture until silylationis complete, incorporating in the mixture, a weak amine, in amount toprovide a molar ratio of from about 0.75 to 1.25 moles thereof per moleof 6-aminopenicillanic acid, and then incorporating into the resultingmixture a mineral acid salt of a weak amine in at least molarconcentration to inactivate the byproduct alkylamine or ammoniafurnished in the silylation reaction.
 16. A method of preparing asilylated derivative of 6-aminopenicillanic acid, as defined in claim15, wherein: the silylating agent is trimethylsilyldiethylamine.
 17. Amethod of preparing a silylated derivative of 6-aminopenicillanic acid,as defined in claim 15, wherein: the silylating agent ishexamethyldisilazane.